Myocardial innervation imaging: MIBG in clinical practice
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Myocardial innervation imaging: MIBG in
clinical practice
p
ALBERTO AIMO1,2 and ALESSIA GIMELLI3
IMAGING 1
Cardiology Division, University Hospital of Pisa, Italy
2
Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
3
Fondazione Toscana Gabriele Monasterio, Pisa, Italy
Received: September 25, 2020 • Accepted: March 17, 2021
REVIEW ARTICLE
ABSTRACT
123
I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to
investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with
interest in many disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy
can capture functional impairment and rarefaction of sympathetic terminals (which manifest as
reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased
sympathetic outflow (which can be visualized as high washout rate). These findings have been
consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a
late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening
arrhythmias over a follow-up of less than 2 years. Despite these promising findings, 123I MIBG
scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk
stratification, and has then never entered the stage of widespread adoption into current clinical
practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction,
genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several
other conditions characterized by impaired sympathetic myocardial innervation. In the present
chapter we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the current
unresolved issues, and the possible directions of future research.
KEYWORDS
MIBG, cardiac innervation, imaging, sympathetic function, heart failure
MIBG imaging: general concepts
A brief history of MIBG
Cardiovascular function continuously adapts to changing demands by means of the
autonomic nervous system, which includes the sympathetic and parasympathetic arms,
which exert stimulating or inhibitory effects on target tissues. The effects of the sympathetic
IMAGING (2021) nervous system are primarily mediated by the release of the neurotransmitter norepi-
DOI: 10.1556/1647.2021.00021
nephrine (NE) from presynaptic nerve terminals, and its binding to adrenergic receptors
© 2021 The Author(s) [1]. Around 80–90% of NE released by sympathetic nerve terminals is re-uptaken into
presynaptic nerve terminals through the uptake-1 mechanism, i.e. the NE transporter
p
Corresponding author. Fondazione (NET) [2]. Once inside the nerve terminal, NE is transported into vesicles through vesicular
Toscana Gabriele Monasterio, Via
monoamine transporter 2 or is metabolized by monoamine oxidase. The remainder of NE
Moruzzi 1, 56124 Pisa, Italy.
E-mail: gimelli@ftgm.it is either be cleared into the circulation or on the postsynaptic side via uptake-2, which
transports NE into extraneuronal tissues, such as the heart, where it is metabolized by
catecholamine-O-methyl-transferase [3].
In the 1960s, guanethidine was developed as an antihypertensive drug. Guanethidine is
transported across the sympathetic nerve membrane by NET and is stored, unmetabolized, in
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2 Cardiac I-MIBG scintigraphy IMAGING
transmitter vesicles, where (at therapeutic concentrations)
ðearly H early MÞ ðlate H late MÞ
replaces NE and then inhibits noradrenergic transmission *100
[4]. Combination of a benzyl group and the guanidine group ðearly H early MÞ
of guanethidine produced metaiodobenzylguanidine This calculation must be corrected for decay to the
(MIBG), which showed a similar affinity and capacity to NE moment of early acquisition.
for NET, and is similarly stored into vesicles [5]. Iodination The early H/M probably reflects the integrity of presyn-
of MIBG with a radioactive isotope enables successful im- aptic nerve terminals and NET function. The late H/M
aging of sympathetic terminals and other neuroectodermally combines information on neuronal function from uptake to
derived cells. The first clinical application of the radiolabeled release through the storage vesicle at the nerve terminals. The
MIBG with 131I was the visualization of the adrenal medulla WR is an index of the degree of sympathetic drive. Therefore,
and different neural crest-derived tumors such as pheo- increased sympathetic activity is associated with high WR
chromocytomas and neuroblastomas [5]. The intense and low myocardial MIBG delayed uptake. Reference values
myocardial uptake observed in these studies led to speculate have been identified in the Japanese Society of Nuclear
that radiolabeled MIBG with 131I could be used for Medicine normal database: early H/M, average 3.1, range
myocardial imaging. However, due to the suboptimal im- 2.2–4.0; late H/M, average 3.3, range 2.2–4.4; WR, average 13,
aging characteristics of MIBG and a less favorable radiation range 0–34% [10]. Early and late H/M decrease with age even
burden, radiolabeling of MIBG with 123I was preferred for in normal subjects, while WR is not affected by age [11].
diagnostic purposes. In 1981 Kline et al. used MIBG scin- The use of cardiac SPECT may provide information on
tigraphy to image myocardial innervation in 5 healthy regional MIBG distribution. SPECT images can be acquired
subjects, and concluded that MIBG had the potential to after planar images with early and delayed acquisition. A
provide semiquantitative information on myocardial cate- tomographic reconstruction is performed, and correction for
cholamine content [6]. scatter or tissue attenuation may be applied. MIBG distri-
bution in the SPECT study is similar to that of perfusion
imaging tracers, but the inferior accumulation is relatively
Basic information for clinicians lower in an MIBG study, particularly for aged individuals
[12]. Myocardial regions displaying no uptake of MIBG can
Usually, MIBG is administered intravenously after blockade still be viable, as demonstrated by perfusion imaging with a
of thyroid uptake of free 123I through either 500 mg potas- tracer such as 99mTc-tetrofosmin.
sium perchlorate or 200 mg potassium iodide (10% solu- Several drugs are known, or may be expected, to interfere
tion), although this could be omitted considering that 123I is with organ MIBG uptake. In a review of the literature on drug
a gamma emitter with a short half-life [7]. A standard dose is interactions with MIBG uptake, the only medications for
185 MBq for cardiac imaging, corresponding to an effective which level of evidence was judged high were labetalol and
dose of 2.4 mSv in adults [8]. The administered dose of reserpine. Level of evidence was judged medium for tricyclic
MIBG can be down to 55–111 MBq when using the new antidepressants, calcium channel blockers, and antiarrhyth-
gamma cameras. mics (specifically amiodarone). Evidence was judged sufficient
MIBG is internalized by presynaptic nerve endings of to recommend withholding labetalol and the tricyclic anti-
postganglionic neuronal cells through NET. A 15% energy depressants prior to cardiac MIBG imaging, and to suggest
window is usually used, centered on the 159-keV 123I pho- consideration of withdrawal of sympathomimetic amines and
topeak. Anterior planar images are obtained 15 minutes serotonin-norepinephrine reuptake inhibitors [13]. On the
(early) and 4 hours (late) after injection and stored in contrary, cardiac MIBG imaging can be performed in patients
128p 128 or 256p 256 matrixes with standard single photon on beta-blockers and angiotensin-converting enzyme in-
emission computed tomography (SPECT) camera. Because hibitors or angiotensin receptor blockers (ACEi/ARB) [14].
MIBG is primarily secreted via the kidneys, patients are Withdrawal of beta-blockers (with the possible exception of
encouraged to void frequently to facilitate rapid excretion of labetalol), ACEi/ARB, or other HF medications is then not
the tracer [7]. Importantly, differences in the rate of renal required [7]. Conversely, food containing vanillin and cate-
excretion did not contribute to variability in mediastinal and cholamine-like compounds (such as chocolate) should be
myocardial counts between early and late planar MIBG avoided as they may interfere with MIBG uptake [7].
images [9].
The commonly evaluated parameters on MIBG
scintigraphy are the heart-to-mediastinum (H/M) ratio Potential clinical applications of myocardial
and washout ratio (WR). On anterior planar images, innervation imaging
regions of interest (ROIs) are drawn over the heart (H)
and the mediastinum (M). The average counts in each
Heart failure
ROI are obtained, and the H/M ratio is calculated. The
WR is calculated as the difference between the early Despite considerable advances in drug and device treatment,
and late H/M, as a percentage of the early H/M, or by heart failure (HF) still represents a significant cause of
computing the actual myocardial counts during the morbidity and mortality, and its epidemiological burden is
early and late phases: bound to increase in the next years. HF is by far the
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condition most intensely studied through MIBG imaging, planar scintigraphy and MIBG imaging over techniques such
given the crucial pathogenetic role of sympathetic over- as cardiac magnetic resonance, and the possible role of MIBG
activity in HF with reduced ejection fraction (HFrEF). As of imaging for the selection of candidates to cardiac resynchro-
September 2020, a search for “MIBG” and “heart failure” on nization therapy (CRT), left ventricular assist device (LVAD),
Pubmed yields 556 papers, with a progressive increase in or heart transplantation) [23].
publications since the ‘80s. Many of these papers focused on The degree of cardiac sympathetic stimulation, as eval-
the role of MIBG imaging for risk stratification, and on uated through the WR, yielded additive prognostic signifi-
patients with HFrEF, considering heterogeneous endpoints, cance for fast ventricular arrhythmias to other measures of
but usually cardiac death or major cardiac events. autonomic dysfunction (MIBG findings, heart rate vari-
Myocardial denervation has been consistently associated ability [HRV] on 24-h ECG Holter monitoring and baror-
with a worse prognosis in patients with HF. For example, the eflex sensitivity) over a mean of 32 months [24]. Moreover,
mean H/M ratio in patients who died was typically 0.2–0.3 the presence and extent of an innervation/perfusion
lower than in those who survived. Meta-analyses of pub- mismatch, i.e. denervated but still viable areas, has been
lished studies reported pooled hazard ratios of late H/M consistently associated with increased arrhythmogenicity.
for cardiac death of 1.82 (95% confidence interval [CI] For example, in a cohort of 17 patients with implantable
0.80–4.12; P 5 0.15) and 1.98 for cardiac events (1.57–2.50; cardiac defibrillators (ICDs), the combined assessment of
P < 0.001) [15], and that a low H/M (with threshold ranging innervation/perfusion mismatch and HRV allowed correct
from 1.5 to 1.89) denoted a 5-fold higher risk of cardiac identification of patients at high and low risk for potentially
death (odds ratio [OR] 5.2, 95% CI 3.1–5.7) [16]. Further- fatal arrhythmias [25]. The added value of a dual isotope
more, MIBG uptake was an independent and stronger pre- SPECT protocol (to assess innervation and perfusion) over a
dictor of mortality than late H/M [17], and a high washout simple innervation imaging was questioned by a study on
rate (WR) (from 38 to 53%) was also associated with lethal 116 HF patients referred to defibrillator implantation for
events with a pooled odds ratio of 2.8 (95% CI 1.6–5.0) [16]. primary or secondary prevention, the extent of late MIBG
The H/M or WR emerged as independent predictors of SPECT defects predicted appropriate ICD discharges and
adverse events from LVEF, New York Heart Association cardiac death over 23 ± 15 months, independent from an
(NYHA) class, and natriuretic peptides (NPs) [18]. innervation/perfusion mismatch score [26]. Conversely,
The results of the largest prospective trial examining the perfusion SPECT might hold additive prognostic signifi-
prognostic significance of MIBG imaging in HF were pub- cance to a global assessment of myocardial innervation by
lished in 2010. The AdreView Myocardial Imaging for Risk planar MIBG scintigraphy. In a cohort of 60 ICD patients
Evaluation in Heart Failure (ADMIRE-HF) study enrolled followed for a mean of 29 months, patients with impaired
961 patients with stable HF, LVEF ≤35%, NYHA class II–III MIBG uptake (H/M 12 had a significantly greater event rate (94%)
[19]. Patients with a ventricular pacemaker that routinely than the group with impaired MIBG uptake and preserved
functioned or had received defibrillation (either external or 99m
Tc-tetrofosmin uptake [45%; P < 0.05] and the group
via an ICD), anti-tachycardia pacing, or cardioversion for with preserved uptake of both agents (18%) [27]. We are not
ventricular arrhythmias were excluded [20]. Patients had a aware of studies evaluating whether MIBG imaging can
mean LVEF of 27%, and 66% of them were adjudicated as inform the decision as to whether an ICD should be
having ischemic HF. Over a mean follow-up of 17 months, implanted in borderline cases (for example, in patients
237 subjects (25%) experienced events (cardiac death, life- with non-ischemic etiology and LVEF approaching the 35%
threatening arrhythmias or NYHA class progression), of threshold), or can help predict response to CRT.
which only 25 occurred in the 201 subjects with a late H/M The increased circulating NE levels commonly seen in
≥1.60 (chosen as the lower limit of normal). Two-year event patients with HF and the poor prognosis of individuals with
rate was 15% in patients with H/M ≥1.60 and 37% in those particularly high NE levels are associated with a decreased
with H/M123
4 Cardiac I-MIBG scintigraphy IMAGING
there was no difference in the mean H/M at baseline be- normal subjects, in the whole heart as well as in the remote
tween subjects who did and did not survive, 92% of those myocardium, denoting an increased sympathetic stimulation
who died showed a decrease in H/M between the two MIBG that might contribute to post-MI remodeling [42].
studies. The change in MIBG uptake was a better predictor
of adverse long-term outcome than baseline NE or BNP or
Ischemic heart failure. Many studies on the prognostic value
their changes over 6 months [32].
of MIBG imaging in HF included a significant number of
Open questions:
patients with ischemic etiology [19], while patients with
1. can MIBG be routinely used to select best candidates ischemic HF have been less often specifically evaluated. Car-
for ICD? diac sympathetic nerve activity became progressively more
2. which is the impact of the novel therapeutic options for altered in parallel with HF severity regardless of the underlying
HFrEF on MIBG findings (most notably SGLT2i)? etiology [43], and late H/M was the strongest independent
3. can MIBG imaging help identify patients with a poor predictor of cardiac death in patients with LVEF 26) showed signifi-
coronary syndrome (CCS) have focused on the specific cantly more appropriate ICD therapy (52 vs. 5%, P < 0.01) and
disease entity known as vasospastic angina, where coronary appropriate ICD therapy or cardiac death (57 vs. 10%, P <
vasospasm causes a transient ischemia in the corresponding 0.01) than patients with a small defect (summed score ≤26) at
vascular territory, leading to MIBG defects that persist even 3-year follow-up. An innervation/perfusion mismatch score
when perfusion is restored. Conflicting results have been was a univariate, but not an independent predictor of both
reported on WR values, as a lower WR was associated with endpoints [26]. In a very recent study on patients with
diagnosis of vasospastic angina [33], but a higher WR with ischemic HF (mean follow-up of 18 months), those receiving
an increased risk of recurrent events [34]. Additionally, areas an ICD for secondary SCD prevention had significantly larger
of defective MIBG uptake were found in patients with silent perfusion and innervation defects, while the imaging results
myocardial ischemia [35]. could not predict patients with appropriate ICD therapy
among patients with ICD implants for primary prevention
Myocardial infarction. Following the acute phase of
[46]. Finally, innervation and perfusion defects were evaluated
myocardial infarction (MI), patients can undergo MIBG
also as predictors of response to catheter ablation of ventric-
imaging to assess the consequences of the ischemic insult on
ular arrhythmias in patients with prior MI and low LVEF.
sympathetic nerve terminals. Small-caliber, unmyelinated
Perfusion/innervation mismatch in a specific LV zone was an
fibers are more susceptible to ischemia than cardiomyocytes,
independent predictor of local abnormal ventricular activity
resulting in fiber dysfunction (stunning) or death [36]. The
on electroanatomic mapping, and a significant reduction in
area of defective MIBG uptake is larger than the perfusion
the perfusion/innervation mismatch score after ablation pre-
defect, and the innervation defects persist after revasculari-
dicted a reduction of the arrhythmic burden [47].
zation [37]. The resulting innervation/perfusion mismatch
Take-home message:
may predispose to ventricular arrhythmias [38], as demon-
strated by the fact that the degree of perfusion/innervation 1. A quite limited number of studies have evaluated
mismatch is significantly correlated with the site of earliest MIBG imaging in patients with ischemic heart disease
activation in ventricular tachycardias (VT) [39]. (from CCS to ischemic HF), and the evidence is quite
A recovery from stunning and/or some degrees of rein- fragmentary.
nervation are believed to occur given that a normal MIBG 2. Myocardial ischemia causes enduring innervation de-
uptake was found 14 weeks after MI in dogs [40], and MIBG fects, areas of innervation/perfusion mismatch are pro-
uptake in the peri-infarcted area increased over 12 months arrhythmogenic in the post-MI setting,
in humans [41]. Patients with a recent MI (IMAGING Alberto Aimo and Alessia Gimelli 5
Ventricular arrhythmias and prediction of sudden tomography (PET), respectively [52]. Dysfunctional LV seg-
cardiac death in genetic disorders ments were found to have a normal perfusion but reduced
innervation and glucose metabolism. These last alterations
The evaluation of the integrity of cardiac sympathetic recovered slowly than LV motion [52]. The role of MIBG
innervation by MIBG scintigraphy has been long proposed imaging for patient characterization and risk prediction after
as a valuable method to stratify the risk of ventricular ar- the acute phase remains to be characterized, while there is
rhythmias (VA) and sudden cardiac death (SCD) in patients probably no room for improvement of the diagnostic workup
with structural heart diseases with a genetic etiology, or [53].
arrhythmogenic disorders not associated with functional and
anatomic changes detectable by conventional techniques.
Anthracycline cardiotoxicity
Idiopathic dilated cardiomyopathy. In patients with idio- Among antineoplastic regimens, anthracyclines carry a
pathic dilated cardiomyopathy (DCM), MIBG washout was particularly high risk of cardiotoxicity [54]. Anthracyclines
correlated with baseline LV function, and the late H/M with cause abnormalities in myocardial adrenergic function that
contractile reserve on atrial pacing [48] or contractility precede LVEF decline and overt HF. In animal studies,
during dobutamine stress testing [49]. Furthermore, the late MIBG uptake in myocardial adrenergic neurons was
H/M emerged as the most powerful independent predictor reduced in a dose-dependent way [55], and MIBG imaging
of cardiac death in patients with DCM [44]. In another small proved superior to echocardiography, plasma NE and car-
study, a mismatch between regional innervation and diomyocyte staining in the early detection of doxorubicin-
perfusion was associated with a higher risk of VT [50]. These induced cardiotoxicity [56]. A dose-dependent decrease in
findings have not been replicated, despite their potential MIBG uptake prior to LVEF deterioration was confirmed in
relevance to select patients for defibrillator implantation or humans. In patients with previous exposure to anthracy-
to guide ablation procedures. cline-containing chemotherapy regimens, late H/M dis-
played an inverse correlation with global longitudinal strain
Hypertrophic cardiomyopathy. Hypertrophic cardiomyop- [57], but damage to adrenergic myocardial neurons seemed
athy (HCM) is the most common genetic cardiovascular to persist even in patients recovering from LV dysfunction
disorder, and an important cause of SCD. Preliminary results [58]. At present, the most promising application of MIBG
indicated an important role of cardiac sympathetic nervous imaging in this setting is early diagnosis of anthracycline
innervation in LV function at baseline (HCM patients with cardiotoxicity, but further comparisons with alternative ap-
systolic dysfunction had a significantly lower early MIBG proaches such as speckle tracking echocardiography or high-
uptake than controls with a WR decrease from normal to sensitivity troponins are warranted.
abnormal EF) and during exercise, even if it remains to be
established if MIBG scintigraphy can predict the deterioration Heart transplantation
of cardiac function or other outcomes, most notably SCD.
During heart transplantation, postganglionic sympathetic
nerve fibers of the donor heart are surgically interrupted,
Takotsubo cardiomyopathy resulting in complete denervation [59]. The denervated
heart early after transplantation is a useful model to test the
Takotsubo cardiomyopathy (TTC) is a condition where the
specificity of neuronal imaging agents, as no cardiac uptake
heart takes on the appearance of a Japanese octopus fishing
should be detected in this condition [60]. Sympathetic
pot, and symptoms and signs of MI coexist with no
reinnervation after transplantation was first reported in
demonstrable coronary artery stenosis or spasm. LV func-
animal models [61], and then in human patients evaluated
tion can be remarkably depressed, but usually recovers
with MIBG SPECT as well as with PET tracers [62, 63]. For
within a few weeks. A sudden surge in sympathetic activity is
example, 48% of 23 patients evaluated 1–2 years after
considering as a crucial determinant of disease in TTC. A
transplantation showed a cardiac uptake [60], and reinner-
demonstration of adrenergic hyperactivity in TTC came
vation starts from basal segments, anterior and septal walls
from a study where 123I-mIBG planar scintigraphy was
[62, 63]. Areas of reinnervated myocardium have improved
performed during the subacute phase (median of 8 days after
blood flow regulation, energy substrate use, cardiac perfor-
coronary angiography). Patients (n 5 32) displayed a lower
mance, and exercise capacity [64], but the relationship be-
late H/M and increased WR than control subjects with acute
tween reinnervation and patient survival is uncertain [65].
coronary syndrome. Decreased cardiac MIBG uptake was
attributed to inhibited MIBG reuptake by high epinephrine
levels in the synaptic cleft and/or NET downregulation.
Cardiac amyloidosis
Adrenergic overactivity resolved over time, as demonstrated Systemic amyloidoses are characterized by the extracellular
by late H/M and WR values after a median of 109 days [51]. accumulation of misfolded proteins into the beta-sheet
The relationship among sympathetic innervation, configuration, leading to tissue damage. The two most
myocardial perfusion and glucose metabolism in TTC was common forms are amyloid light-chain (AL) and trans-
evaluated by MIBG gated SPECT, 99mTc-tetrofosmin or 201Tl thyretin amyloidosis (ATTR), the latter due to the deposi-
gated SPECT and 18F-FDG gated positron emission tion of either normal (wild-type ATTR, ATTRwt) or
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6 Cardiac I-MIBG scintigraphy IMAGING
mutated TTR molecules (variant ATTR, ATTRv) [66–68]. innervation defects after PVI on MIBG SPECT images
The heart is the organ most commonly affected in ATTRwt was associated with an increased risk of AF relapses over a
and one of the main sites of light-chain deposition; 6-month follow-up (40% vs. 17% of patients) [74].
furthermore, different mutations in the TTR gene have been The cardiac autonomic system includes thousands of
associated with a prevalent involvement of the heart or the neurons located in ganglionated plexuses (GPs) in the
peripheral nervous system. Manifestations of cardiac epicardial fat pads that project axons to widespread regions
amyloidosis (CA) include left ventricular pseudohyper- of the heart. Four of the 7 main GPs are located around the
trophy and conduction disturbances. Clinical evidence of pulmonary veins, and the results of PVI by radiofrequency
autonomic dysfunction is quite common in ATTRv and AL pulses may depend on effective destruction of these GPs.
amyloidosis, but not in ATTRwt. Sudden cardiac death has a The standard approach to localize the GPs is to apply high-
high incidence and may result from tachyarrhythmias, but frequency stimulation to the presumed GP areas to elicit
more often from electromechanical dissociation or ar- atrioventricular blocks, but this method has low specificity
rhythmias not amenable to defibrillator therapy [66–68]. and sensitivity, is invasive and time-consuming [75]. MIBG
MIBG scintigraphy may allow to assess myocardial imaging has been recently used to localize GPs. Stirrup
innervation in CA [69]. Carriers of TTR gene mutations (n et al. defined a high-resolution CZT SPECT/computed
5 31) displayed a reduced late H/M (IMAGING Alberto Aimo and Alessia Gimelli 7
Summary Table. 123
I-MIBG imaging and cardiac disease: evidence from clinical studies
Patient management
(planning or monitoring of
Diagnosis (early diagnosis or drug/device therapy,
differential diagnosis Risk stratification follow-up)
Planar scintigraphy SPECT Planar scintigraphy SPECT Planar scintigraphy SPECT
Heart failure − − þþþ þþ þ −
Ischemic heart disease
Chronic coronary syndrome þ þ − − − −
Myocardial infarction − − þ þ − −
Ischemic heart failure − − þ þ − −
Ventricular arrhythmias and prediction of sudden cardiac death in genetic disorders
Idiopathic DCM − − þ þ − −
HCM − − − − − −
Takotsubo cardiomyopathy − − − − − −
Anthracycline cardiotoxicity þ − − − − −
Heart transplantation − − − − − −
Cardiac amyloidosis − þ − − − −
Atrial fibrillation − − − − − þ
Diabetes mellitus − − þ − − −
Parkinson's disease and related þ − − − − −
disorders
þþþ, evidence from multiple clinical studies; þþ, evidence from a small number of studies; þ, evidence from one or very few studies;
−, no clear evidence from published studies.
diseases (LBD)” because they share the presence of Lewy influenced by most therapies, contraindications are limited
bodies (cytoplasmic inclusions containing alpha-synuclein to known hypersensitivity to MIBG or MIBG sulphate, and
protein aggregates) in neurons. The main clinical application adverse effects are very rare [7], should be emphasized.
of cardiac MIBG scintigraphy in patients with PD is Furthermore, the role of regional characterization through
currently the differential diagnosis between PD and other MIBG SPECT deserves further consideration as a tool to
parkinsonisms with high sensitivity and specificity [79]. capture early stages of myocardial denervation, possibly
missed by planar scintigraphy, or to identify regions of
innervation/perfusion mismatch when combined with
Future perspectives perfusion SPECT. The latest developments in SPECT im-
aging, namely the CZT technique and digital detector-based
The main applications of MIBG and SPECT for cardiac SPECT/CT, can also obviate the need for ME collimators.
sympathetic imaging are recapitulated in the Summary PET imaging of cardiac sympathetic innervation has many
Table. One of the possible causes why MIBG cardiac im- advantages over MIBG SPECT, including a greater spatio-
aging has not been widely adopted in clinical practice, even temporal resolution and well-validated attenuation correc-
for the characterization of patients with HF, is the fact that tion, the availability of many tracers that allow to explore
acquisition protocols remain quite heterogeneous in terms of both pre- and post-synaptic terminals, and the possibility of
tracer doses, timing of acquisition, ROI drawing, and use of quantitative tracer uptake [1]. On the other hand, the need
LE instead of ME collimators, despite a proposal for stan- for an on-site cyclotron for all 11C-labelled tracers will
dardization [7]. Lack of standardization is likely a major greatly limit the applicability of PET in current clinical
source of heterogeneity among study results, and may help practice, and prompts a search for the settings where it can
explain why this technique has not gained widespread be replaced by MIBG SPECT.
adoption in clinical practice, and has not entered even HF
guidelines in spite of the evidence that MIBG holds prog-
nostic significance in this condition. The only exception is a Conflicts of interest: None.
guideline by the Japanese Circulation Society Joint Working
Group, which includes a class I recommendation for MIBG Permissions: Not required.
imaging for the assessment of severity and prognosis of HF
[80]. A standardized approach to MIBG acquisition, possibly ABBREVIATIONS AND ACRONYMS
stimulated by novel and updated recommendations, can ACEi/ARB angiotensin-converting enzyme inhibitors
then be envisaged. The strengths of MIBG imaging, i.e. the or angiotensin receptor blockers
fact that early and late acquisitions are relatively rapid, ra- ADMIRE-HF AdreView Myocardial Imaging for Risk
diation exposure is limited (with an effective dose of less Evaluation in Heart Failure
than 1 mSv when using CZT cameras), results are not ADMIRE-HFX extension study of ADMIRE-HF
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8 Cardiac I-MIBG scintigraphy IMAGING
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